Brief in Brief (TL;DR)

What do we know:
The brain area called the substantia nigra (SN) plays important roles in trial-and-error learning and the control of movement. The movement disorder Parkinson's disease is caused by the loss of SN cells that release dopamine, known as DA cells. The SN also contains a different type of cells known as GABA cells. From animal studies, it is known that DA and GABA cells have different functions in the SN.

What don’t we know:
Whether, in the human SN, these two cell types also serve different functions.

What this study shows:
When humans play a game that involves trial-and-error learning, DA and GABA cells respond differently to rewarding experiences.

What we can do in the future because of this study:
Having established that there are distinct groups of neurons, we can begin to explore how they each contribute to normal and abnormal brain function.

Why you should care:
Dysfunction of the SN occurs in many brain disorders, including Parkinson's disease (in which DA cells die) and schizophrenia. Understanding the normal functions of the cells that make up the SN can thus help us understand and potentially treat these brain disorders.

Brief for Non-Neuroscientists

The substantia nigra (SN) has at least two neuron types: DA neurons, which release the neurotransmitter dopamine, and GABA neurons, which release the neurotransmitter GABA. Animal studies indicate that these cells play distinct roles in a variety of tasks, including trial-and-error learning and motor control. Animal studies have also shown that these neurons have different electrical properties. For example, DA cells tend to fire more slowly than GABA cells. In this study, the scientists recorded from the SN of human patients undergoing surgery for Parkinson's disease while the subjects played a video game involving trial-and-error learning. In the past, it has been difficult to study the activity of DA cells versus GABA cells in the human brain because these cells are anatomically intermingled. This challenge was overcome by using the distinct electrical properties of DA and GABA cells in the SN, rather than physical features or location, to classify them. They found that human DA and GABA cells do indeed respond differently when patients encounter positive experiences in their video game. This result confirms that there are two subpopulations of cells with different roles in the human SN and gives neuroscientists a new tool to distinguish these subpopulations in future studies.

Brief for Neuroscientists

The substantia nigra (SN) is composed of two anatomically intermingled subareas known as the pars compacta and the pars reticulata, which are key nodes of the basal ganglia system for learning from trial-and-error (reinforcement learning) and controlling movement. Pars compacta and pars reticulata are preferentially enriched for neurons that release the neurotransmitters DA and GABA, respectively. Non-human studies indicate that DA and GABA cells in these two areas play functionally distinct roles in the basal ganglia; however, it is not known whether the same is true in the human brain, partly because these cells tend to be anatomically intermingled. In this study, Ramayya and colleagues recorded from the SN of human patients undergoing surgery for Parkinson's disease, which involves placement of microelectrodes near the SN. The patients played a video game in which they had to learn by trial-and-error which symbols on the screen would give them the most number of virtual points. After each choice, subjects were given either positive or negative feedback. Recorded cells were classified as DA or GABA cells based on their firing rate and waveform: from animal studies, DA cells are known to have low firing rates and wide spike waveforms, whereas GABA cells have tonically high firing rates and narrower spike waveforms. They found that DA and GABA cells differed in their responses to positive feedback in the game. Whereas DA cells tended to respond with a quick burst of activity soon after feedback (within ~250-500 ms), GABA cells responded more slowly, with elevated firing rates that occurred up to 1000 ms after feedback. These results confirm the existence of two functionally distinct subpopulations of neurons in the human substantia nigra and suggest that a combination of firing rate and waveform may be a useful way to classify DA and GABA cells in vivo for future studies.